tbuckley/cabot-search huggingface dataset:
Abstract 5238: The functional role of promoter germline variants in breast cancer susceptibility genes
Authors: Nelly Arlene Arroyo, Lenin J. Godoy, Julie Dutil
Journal: Cancer Research (2023)

Abstract It is estimated that inherited deleterious or pathogenic germline variants in high- to moderate- penetrance breast cancer (BC) susceptibility genes such as BRCA1, BRCA2, STK11, CDH1, ATM, PALB2, and CHEK2 may explain up to 27% of the BC cases. For the remaining cases, BC develops as a result of the complex interaction between environmental and lifestyle risk factors as well as inherited familial predisposition. While low penetrance genetic variants have limited impact on BC risk when taken individually, their combined effect on polygenic risk scores may provide a risk elevated enough to justify clinical actions. Most of the previous work in hereditary breast cancer research has focused on variants located in the coding region of the genes and as a result, there is an abundance of information on the functional interpretation of such variants, while information on regulatory variants remains limited. The goal of this study was to assess the functional impact of germline variants in the promoter region of BC susceptibility genes on gene expression level. Genes evaluated include CDH1, STK11, and bidirectional promoter genes ATM/NPAT and PALB2/DCTN5. A bioinformatics approach was developed to identify and prioritize variants based on conservation level and predicted binding of transcription regulatory proteins. Selected variants will be introduced into pGL3 constructs harboring the promoter of interest using site-directed mutagenesis followed by transfection into HEK293T cells. Dual-glo luciferase expression assays are used to measure levels of promoter activities. Expression levels from promoters containing genetic variants are compared with those from constructs containing the reference sequence. The reference constructs for STK11 and CDH1 containing the genes complete promoters demonstrated functional activity. For bidirectional promoters, forwards and reverse construct were tested. Forward ATM/NPAT and PALB2/DCTN5 constructs showed luciferase expression under the influence of ATM and DCTN5 respectively. Work is on the way to assess promoter activity of the reverse complement sequence of those promoters and determine the impact of 13 candidate variants on the strength of these promoters. At the clinical level, identifying germline variants that contribute to BC risk could help better define BC risk in women with negative hereditary cancer genetic test results. Citation Format: Nelly Arlene Arroyo, Lenin J. Godoy, Julie Dutil. The functional role of promoter germline variants in breast cancer susceptibility genes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5238.
Abstract 4452: FASN inhibition overcomes immune evasion by upregulating MHC-I in hepatocellular carcinoma
Authors: Jiao Huang, Wai Ying Tsang, Xiaona Fang, Yu Zhang, Jie Luo, Lanqi Gong, Baifeng Zhang, Ching Ngar Wong, Beilei Liu, Jinlin Huang, Yuma Yang, Shan Liu, Zhihong Li, Xinyuan Guan
Journal: Cancer Research (2023)

Abstract Immune evasion is one of the important factors leading to the progression of hepatocellular carcinoma(HCC). Restricted antigen presentation by decrease of MHC-I remains a huge barrier to triggering an immune attack. However, knowledge is limited on how to enhance antigen presentation of cancer cells. Here we identify that FASN inhibition by shRNA and inhibitors could boost MHC-I level on HCC cell surface. FASN deficiency also promotes antigen presentation and augments CD8+ T cell cytotoxicity. Mechanistically, FASN knock-down decreases the degradation of MHC-I in lysosomes. Moreover, ZDHHC3-mediated palmitoylation participates in this process. In vivo, orthotopic HCC mouse model shows that Fasn knock-down greatly improves the cytotoxicity of tumor-infiltrating CD8+ T cells and suppresses HCC tumor growth, indicating that inhibiting FASN is a promising way to enhance the efficiency of immunotherapy in HCC. Citation Format: Jiao Huang, Wai Ying Tsang, Xiaona Fang, Yu Zhang, Jie Luo, Lanqi Gong, Baifeng Zhang, Ching Ngar Wong, Beilei Liu, Jinlin Huang, Yuma Yang, Shan Liu, Zhihong Li, Xinyuan Guan. FASN inhibition overcomes immune evasion by upregulating MHC-I in hepatocellular carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4452.
Abstract 6251: High expression level of GSK3β in basal triple negative breast cancer: Effects of the HDAC inhibitor, vorinostat
Authors: Beverly D. Lyn-Cook, Fatemeh Nouri Emamzaden, Beverly Word, George Hammons
Journal: Cancer Research (2023)

Abstract High expression levels of glycogen synthases kinase 3 beta (GSK3β) have been correlated with poor prognosis in triple negative breast cancer (TNBC) patients. GSK3β is a multifaceted kinase and is a key regulator of a number of cellular processes. It is known to function as a positive regulator of epithelial-mesenchymal transition (EMT). Usually, cells that undergo EMT are known to acquire stem cell properties and these cells have properties that are known to be resistant to chemotherapies. Inhibition of GSK3β has been shown to decrease markers of EMT and reduce cancer stem cells. High levels of GSK3β were found in the basal-2 subtype of triple negative breast cancer cells, HCC1806. Histone deacetylases (HDACs) are expressed at high levels in some cancers, including TNBC. In this study, vorinostat, a histone deacetylase inhibitor, was shown to down regulate GSK3 expression in HCC1806 cells at both the gene and protein level using qPCR and western blots. Furthermore, cancer stem cells (CSC) cell markers CD44/CD24 using flow cytometry and immunostaining were significantly decreased. Previous studies published from our laboratory have shown vorinostat’s ability to decrease TNBC cells invasion compacity, as well as cell growth. This study suggests that targeting GSK3β may be a potential therapeutic target for certain subtypes of TNBC. Triple negative breast cancer remains one of the most aggressive breast cancers, often having a high mortality rate in younger women. Citation Format: Beverly D. Lyn-Cook, Fatemeh Nouri Emamzaden, Beverly Word, George Hammons. High expression level of GSK3β in basal triple negative breast cancer: Effects of the HDAC inhibitor, vorinostat [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6251.
Abstract 5223: Circulating lipoprotein lipids and colorectal cancer risk: A Mendelian randomization analysis from the GECCO consortium
Authors: Lili Liu, Wanqing Wen, Jirong Long, Themistocles L Assimes, Luis Bujanda, Stephen B Gruber, Sébastien Küry, Brigid Lynch, Conghui Qu, Minta Thomas, Emily White, Michael O. Woods, Ulrike Peters, Wei Zheng
Journal: Cancer Research (2023)

Abstract Background Conventional observational studies have reported conflicting results regarding the association between low density lipoprotein cholesterol (LDL-C) and risk of colorectal cancer (CRC). We conducted a Mendelian randomization analysis to address this association. Methods Single-nucleotide polymorphisms (SNPs) associated with five blood lipids (total cholesterol, HDL-C, high-density lipoprotein cholesterol [HDL-C], non-HDL-C, and triglyceride) were obtained from a genome-wide association study (GWAS) meta-analysis of European ancestry in the Global Lipids Genetics Consortium (GLGC, N ≤ 1 319 982), and two lipids (apolipoprotein A1 and apolipoprotein B) from a GWAS in the UK Biobank (UKB, N ≤ 441 016). Summary statistics were obtained for these SNPs from a GWAS of CRC in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) including 34,869 cases and 29,051 controls. Associations with CRC risk per one standard deviation increase in the genetically predicted lipids level were generated using inverse-variance weighted random-effects models. Results No overall association was observed between genetically predicted levels of blood lipids and CRC risk. However, increased risks were observed for all LDL-C related traits among women, including total cholesterol (OR = 1.10; 95%CI = 1.02, 1.18), LDL-C (1.07; 1.00, 1.14), non-HDL-C (1.09; 1.02, 1.16), and apolipoprotein B (1.11; 1.02, 1.21); whereas no significant association was found among men. Similar but ostensibly stronger associations of these traits were seen with distal colon cancer cases, with no significant association showing on proximal colon or rectum cancer cases. We also observed similar positive associations of LDL-C related traits among those having CRC before their 50 years. Of note, risk reduction was found for apolipoprotein A1, a major component of HDL-C, in these early-onset cases (0.87; 0.78, 0.98). Conclusion Results from this study suggest that high circulating LDL-C levels may increase the risk of CRC, particularly cancer of the distal colon, and the association may differ by sex and age at CRC onset. Key words: Blood lipids; colorectal cancer; Mendelian randomization. Citation Format: Lili Liu, Wanqing Wen, Jirong Long, Themistocles L Assimes, Luis Bujanda, Stephen B Gruber, Sébastien Küry, Brigid Lynch, Conghui Qu, Minta Thomas, Emily White, Michael O. Woods, Ulrike Peters, Wei Zheng. Circulating lipoprotein lipids and colorectal cancer risk: A Mendelian randomization analysis from the GECCO consortium. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5223.
Abstract 6279: CTS2190, a next-generation epigenetic inhibitor for targeting type I PRMT deregulated human tumors
Authors: Hui Shi, Xingnian Fu, Qiugeng Ouyang, Jiaxin Huang, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu
Journal: Cancer Research (2023)

Abstract Methylation of arginine residues by protein arginine methyltransferases (PRMTs) is involved in the regulation of fundamental cellular processes. Type I PRMTs are frequently overexpressed in a variety of human cancers and associated with poor prognosis. Knockout (KO) of Prmt1 in mice results in decreased asymmetric dimethylarginine (ADMA) on cellular proteins, together with increased monomethylarginine (MMA) and symmetric dimethylarginine (SDMA) (Dhar et al., 2013). A structure-based drug discovery effort led to the identification of CTS2190 that showed single-digit nanomolar enzymatic inhibitory activity on type I PRMTs. Here, we report the development and preclinical characterization of CTS2190, a potent, orally bioavailable small molecule type I PRMT inhibitor. CTS2190 demonstrated strong cellular proliferation inhibitory activity in a large, diverse panel of human hematological and solid tumor cell lines across several lineages. In vivo, oral CTS2190 administration once daily resulted in tumor regression in a variety of xenograft (both CDX and PDX) models across different lineages with good tolerance. The anti-tumor activity was dose-dependent and correlated with the inhibition of type I PRMT activity as measured by decrease in ADMA and increase in MMA. In summary, CTS2190 is a promising type I PRMT inhibitor and clinical trial is underway to explore the proof-of-concept anti-tumor benefit for patients. Citation Format: Hui Shi, Xingnian Fu, Qiugeng Ouyang, Jiaxin Huang, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. CTS2190, a next-generation epigenetic inhibitor for targeting type I PRMT deregulated human tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6279.
Abstract 5226: Exome-wide association study identifies coding variant in IL17RA associated with survival in cancer patients treated with immunotherapy
Authors: Sam O. Kleeman, Michael Chan, Matthew Chvasta, Tobias Janowitz
Journal: Cancer Research (2023)

Abstract Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 and CTLA4 are effective treatments in multiple cancer types, but durable responses are seen only in a minority of patients. Resistance to ICI is likely to reflect a combination of tumor-intrinsic, such as tumor mutational burden, and tumor-extrinsic factors, such as systemic immune suppression and host genetics. With the advent of large-scale germline genotyping studies, there is emerging evidence that host-specific genetic factors can substantially modify both disease risk and responsiveness to therapy. There has been limited characterization to date of the interaction between host genetics and response to ICI. Here, we perform harmonized mutation calling in available normal exome sequencing from 668 metastatic cancer patients treated with ICI (derived from n=7 studies, spanning n=3 cancer types and PD-1/PD-L1/CTLA4-directed therapy) and performed exome-wide association studies in European ancestry patients. For each cancer type (melanoma, renal cell carcinoma, urothelial carcinoma), we conducted exome-wide Cox regression (with PC1-4 and sex as covariates) to identify coding single-nucleotide polymorphisms (SNPs) associated with overall survival (OS). On fixed-effect meta-analysis, we identified a single coding variant (rs140221307, C allele, MAF 0.5% in European populations) that met genome-wide significance (p=1.11 × 10−15, HR=4.86, 95% CI 3.30-7.15). This SNP causes a substitution of Trp to Arg at amino acid 320 at the interface between the transmembrane and extracellular domains of interleukin 17 receptor A (IL17RA). While the secretion mechanism is uncharacterized, soluble IL17RA can be readily detected in plasma and the survival-reducing variant is associated with substantially elevated plasma IL17RA (p=1.90 × 10−9, beta=1.01, Sun et al. 2018) as well as reduced monocyte counts in UK Biobank (p=2.20 × 10−308, beta=-0.60). We have established a prime editing strategy to induce this variant in cultured human monocytes to investigate its biochemical and functional consequences, and are performing validation studies in independent patient cohorts. Soluble IL17RA would be expected to function as a decoy receptor to antagonize IL17/IL17RA signaling, and so these data suggest that activation of IL-17 receptor signaling might improve responsiveness to ICI therapy. Citation Format: Sam O. Kleeman, Michael Chan, Matthew Chvasta, Tobias Janowitz. Exome-wide association study identifies coding variant in IL17RA associated with survival in cancer patients treated with immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5226.
Abstract 6282: EP102: Pharmacological inhibition of METTL3 arrests tumor progression and prolongs survival in CDX and PDX models of AML
Authors: Graeme Fraser, Catherine Sorlet, Nicolas Parmentier, Elodie Brunel, Anne-France Hartiel, Killian Oukoloff, Guillaume Dutheuil
Journal: Cancer Research (2023)

Abstract METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-6-methyladenosine (m6A), the most abundant modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML)1. EPICS has discovered and optimized a small molecule inhibitor of METTL3 (“M3i”). M3i was shown to inhibit the enzymatic activity of METTL3 (IC50 = 2 nM, SPA assay) and inhibit the presence of intracellular m6A in a cell-based assay (IC50 = 8 nM, Calu6). The anti-proliferative effects of METTL3 was demonstrated in a spheroid model (NCIH-560, IC50 = 100 nM) as well as cell viability assays in various AML (Kasumi-1, IC50 = 30 nM; LEXF 41283, IC50 = 46 nM; MV-4-11, IC50 = 248 nM) and solid tumor (Calu6, IC50= 6 nM; Caov3, IC50 = 27 nM) cell lines. In vivo efficacy was evaluated in a disseminated xenograft model using established systemic MV-4-11-Luc-mCh-Puro2 in female NSG mice where M3i (30 mg/kg, i.p., QDx31 days) significantly (p&amp;lt;0.01, relative to vehicle control) inhibited cancer progression as measured by in-life imaging in addition to flow cytometry of hCD45+ cells in bone marrow, blood and spleen; M3i had minimal effects on hematopoiesis in this model with no significant changes in RBCs, WBCs and neutrophils, but an increase in platelets (measured by IDEXX). In an orthotopic, patient-derived xenograft model of AML (LEXF 41283, intratibial implantation, female NSG mice), M3i (30 mg/kg, i.p., QDx91 days) significantly prolonged survival (p&amp;lt;0.01, relative to vehicle control) with a commensurate absence of hCD45+ cells following compound treatment. These results confirm that the pharmacological inhibition of METTL3 is a viable strategy for the treatment of AML and support the additional exploration of the role of METTL3 inhibitors in alternate blood cancers as well as solid tumors. Citation Format: Graeme Fraser, Catherine Sorlet, Nicolas Parmentier, Elodie Brunel, Anne-France Hartiel, Killian Oukoloff, Guillaume Dutheuil. EP102: Pharmacological inhibition of METTL3 arrests tumor progression and prolongs survival in CDX and PDX models of AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6282.
Abstract 1259: Disturbing the Siglec-Sialoglycan axis to target myeloid- derived suppressor cells in the tumor microenvironment
Authors: Ronja Wieboldt, Andreas Zingg, Emanuele Carlini, Anastasiya Börsch, Heinz Läubli, Natalia Rodrigues Manutano
Journal: Cancer Research (2023)

Abstract Background: Overexpression of sialic acids on glycans, called hypersialylation is a common alteration in cancer that drives immune evasion via interaction with Sialic acid-binding immunoglobulin-like lectin (Siglec) immunoregulatory receptors on tumor-infiltrating immune cells. Myeloid derived suppressor cells (MDSCs) generated by cancer-induced aberrant myelopoiesis are highly immunosuppressive cells inhibiting immune cells via direct interaction or secretion of suppressive cytokines. Targeting the complex suppressive tumor microenvironment (TME) remains a challenge. Methods: Siglec expression of murine and human MDSCs in healthy conditions and tumor setting was assessed by flow cytometry. Functional analysis of Siglec-E knockout on MDSCs in mice was evaluated using SigE-LysMCre mice and suppressive capacity was tested in vitro in combination with SiglecE blocking and cleavage of Sialoglycans using Sialidase. Results were confirmed in the human setting using an in vitro assay to generate MDSC-like cells including RNA-Sequencing and a MDSC suppression assay with cancer-derived MDSCs. Results: MDSCs express multiple inhibitory Siglec receptors in humans and mice. Knockout of SiglecE in the myeloid compartment in vivo resulted in prolonged survival and increased T cell infiltration compared to litter mates expressing Siglec-E. Of note, desialylation of MDSCs and Siglec-E blocking in vitro reduced MDSCs suppressive function against T cells. Similarly, reducing Sialoglycans by Sialidase in human MDSC generated in vitro resulted in increased suppressive capacity and downregulation of functional MDSC markers on RNA level. Findings were validated with lung cancer patient derived MDSCs. Conclusion: Our results provide first insights into the importance of the Siglec-Sialoglycans axis to modulate MDSCs in the TME. Targeting glycosylation of MDSCs with Sialidase reduces their suppressive capacity making it a powerful approach to improve cancer immunotherapy. Further studies are needed to reveal the underlying mechanisms. Citation Format: Ronja Wieboldt, Andreas Zingg, Emanuele Carlini, Anastasiya Börsch, Heinz Läubli, Natalia Rodrigues Manutano. Disturbing the Siglec-Sialoglycan axis to target myeloid- derived suppressor cells in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1259.
Abstract 521: Discovery of novel TNKS inhibitors through structure-based virtual screening
Authors: Hwani Ryu, Hye-Ran Seo, Hyo Jeong Kim, Jiyeon Ahn
Journal: Cancer Research (2023)

Abstract More than 80% of colorectal cancers (CRCs) have somatic mutations in the adenomatous polyposis coli (APC) gene, which affects abnormal WNT/β-catenin signaling. Since inhibition of tankyrases (TNKS1 and TNKS2) belonging to the poly(ADP-ribose) polymerase family stabilizes AXINs and induces degradation of β-catenin, drug development as a therapeutic target for APC-mutated CRCs is required. To identify selective small molecule inhibitors of TNKS, we performed pharmacophore modeling and structural docking studies targeting nicotinamide, adenosine, and both binding subsites of TNKS. Among the 8 million compounds, 149 of the nicotinamide site binders, 23 of the adenosine site binders, and 15 of the dual-site binders of TNKS were selected through computer-based virtual screening. Using in vitro TNKS1 and TNKS2 enzyme assays, we identified that TI2-N17 and TI3-D11 significantly inhibited TNKS1 and TNKS2 enzyme activities at low nanomolar levels. TI2-N17 and TI3-D11 stabilized AXIN2, reduced active β-catenin, and downregulated β-catenin target genes in COLO320DM, APC-mutated CRC cells. Both compounds exhibited anticancer effects on COLO320DM and SW403 cells. In addition, the combination treatment of 5-Fluorouracil (5-FU), an anticancer agent for CRC patients, and these compounds synergistically inhibited the proliferation of CRC cells compared to single compound treatment. Our findings demonstrated that TI2-N17 and TI3-D11 are therapeutic candidates targeting TNKS for APC-mutated CRCs treatment and suggested that the combined treatment with the compounds and 5-FU chemotherapy may be an effective therapeutic strategy for APC-mutated CRCs. Based on these compounds, further study will develop potent and selective TNKS inhibitors by designing and synthesizing novel derivative compounds. Citation Format: Hwani Ryu, Hye-Ran Seo, Hyo Jeong Kim, Jiyeon Ahn. Discovery of novel TNKS inhibitors through structure-based virtual screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 521.